Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) is soliciting applications to support existing cohorts to address how pre-, peri-, and post-natal environmental exposures impact childhood development and health outcomes as part of the Environmental influences on Child Health Outcomes (ECHO) program. Increasing evidence suggests that exposures early in life (e.g., social environment, maternal behavior, nicotine, diet, microbiome) can result in health deficits and lead to life-long consequences. The purpose of this FOA is to leverage and build upon existing cohort infrastructure to prospectively investigate the role of early life exposures and underlying biological mechanisms in childhood health and disease. This will advance our understanding of how the in utero and early post-natal environments impact childhood outcomes and influence the child's predisposition for health, resilience, and disease. The ultimate goal is to identify critical periods of development that are impacted by multi-level exposures, and identify opportunities to mitigate risk of disease and maximize health.

This FOA runs in parallel with companion FOAs that solicit applications for the Coordinating Center (RFA-OD-16-006), Data Analysis Center (RFA-OD-16-005), Patient/Person Reported Outcomes Core (RFA-OD-16-003), Administrative Supplements to the Children's Health Exposure Analysis Resource (CHEAR) (PA-16-046), and IDeA States Pediatric Clinical Trials Network (RFA-OD-16-002 and RFA-OD-16-001), and a Genetics Core to be released in FY17.

Funding for an exploratory UG3 stage will be used for planning, feasibility testing, and developing study documents, including the study protocol and Manual of Procedures. UG3 projects that have met milestones will be administratively considered for transition to the UH3 implementation phase. Applicants responding to this FOA must address objectives for both the UG3 and UH3 phases.

Applicants are encouraged to pre-assemble more than one cohort in their applications.

NIH is establishing the new Environmental influences on Child Health Outcomes (ECHO) program to address the longitudinal impact of pre-natal, peri-natal, and post-natal environmental exposures on pediatric development and health outcomes with high public health impact. To do so, NIH will support multiple synergistic, longitudinal studies using extant cohorts that represent various environmental exposures (e.g., physical, chemical, biological, behavioral, social). All longitudinal studies will share standardized prospective data collection to address research questions that focus on four key pediatric outcomes. The program will be overseen by a NIH Program Director, a Steering Committee, and an External Scientific Board. ECHO is being solicited through 7 FOAs, including this FOA that is focused on leveraging of existing cohorts to study early life exposures in children's health and disease.

ECHO is focused on key outcomes associated with early life exposures. For the purposes of this initiative, early life is defined as the period from preconception, fetal life, birth, and up to age 5 years old. There is no restriction on the current age range of cohort members, but all applicants must show that the proposed cohort already has early life exposure data and/or can collect high-quality data on early life exposure(s) among cohort participants. The scientific merit of the early life exposure data proposed and the value that a cohort would bring to the ECHO Consortium will be evaluated in peer review.

Successful prevention strategies of childhood disease require a clear definition of incident cases and differentiation from pre-clinical stages of disease. Longitudinal collection of multiple types of data (clinical, diagnostic, and molecular) can inform the trajectory of disease processes and/or age-related changes. Leveraging and combining rich extant datasets from multiple longitudinal cohorts provide a unique opportunity to enhance research in environmental origins of disease, by increasing the power of observations that goes beyond one cohort, one exposure, and one disease. Combining cohorts will help us to efficiently define and understand typical growth and development in children by:

• Improving understanding of the natural history of healthy development and factors predisposing to the development of disease
• Providing a valuable synthetic cohort that can be used as a comparison group for incident cases of childhood disease.
• Advancing our understanding of how early life exposures influence child health outcomes via biological mechanisms.

This and the companion FOAs will form a consortium of investigators to evaluate the effects of early life environmental exposures (including in-utero exposures) on child development and health outcomes through investigation of existing data, exposure analysis of existing and/or prospectively-collected biospecimens, and collaborative standardization of prospective data collection from ECHO's multiple extant cohorts. Combining larger pre- and post-natal cohorts with more selective, high-risk (e.g. of asthma, obesity) pre-, peri- and/or post-natal cohorts will permit the development of a large dataset that can serve as a base cohort for studying typical development and questions related to population-based risk and also serve as a way to examine potential risk factors for diseases/disorders of childhood.

In response to this FOA, investigators with relevant cohorts should propose hypotheses about the impact of early life exposures on child development, health, and disease outcomes during childhood.

Characteristics of cohorts may include, but are not limited to:

• Cohorts that were initiated in pregnancy and have followed outcomes in the offspring.
• Cohorts that were initiated post-partum and have continued to assess the offspring.
• Cohorts that ended data collection of pre-, peri-, or post-natal data on women and offspring, but can demonstrate the capability to recontact and follow up the original sample.
• Cohorts that are currently recruiting and/or assessing pregnant or post-partum women and their offspring.

As investigators in ECHO, cohort leaders will interact with the Coordinating Center (CC), Data Analysis Center (DAC), and Children's Health Exposure Analysis Resource (CHEAR), Genetics, Patient/Person Reported Outcomes (PROs) Cores to design a multi-cohort protocol to answer scientific questions of how early life exposures influence childhood health for each of the focus areas. This collaborative protocol will be implemented across all ECHO focus-area cohorts and include standardized procedures for prospective collection of the following Core Elements listed below.

Cohort applicants should include data collection plans for at least one of the four key development and health outcome Focus Areas, while addressing how future data and biospecimen collection might inform the other areas:

1) Upper and/or lower airway (e.g. asthma, allergies, sleep-disordered breathing)

2) Obesity (e.g. nutrition, metabolic risk factors, activity level)

3) Pre-, peri, and post-natal outcomes (e.g. birth defects, prematurity, neonatal/infant mortality)

4) Neurodevelopment (e.g. attention, cognition, emotion, social/language/behavioral development)

In the UG3 phase, applicants should leverage retrospective and newly collected prospective data from longitudinal cohorts that have existing maternal-fetal-, perinatal-, and/or early postnatal-relevant clinical data and biospecimens for exposures analyses of relevance to at least one of the four Focus Areas (listed above). In the UH3 phase, cohorts will participate in standardized prospective data collection across all cohorts, with a focus on integrating the retrospective and prospective data and integrating analyses across cohorts. Applicants are encouraged, but not required, to pre-assemble more than one existing cohort prior to submission and are strongly encouraged to work with biostatisticians when developing a research plan. Basic mechanistic studies that can only be done using samples from the human cohort(s) are encouraged in both UG3 and UH3 phases.

The initial UG3 phase should support:

• Evaluation of ability to recontact participants for consent and/or reconsent of the prospective data and biospecimen collection
• Pilot scale evaluation of the ability to test hypotheses of early life exposures on child health outcomes through the analysis of archived biospecimens (e.g. DNA extraction, quality of biospecimens)
• Collaborative Steering Committee development of a multi-cohort protocol including agreement on assessments for prospective follow-up
• Harmonization of existing data from extant cohorts

The UH3 phase of the application should focus on how the applicant could add to the ECHO consortium, and in what ways the ECHO consortium (with anticipated > or = 50,000 subjects) could examine the influence of multi-level environmental exposures on childhood health outcomes, using both retrospective data and prospective data. Of particular interest would be applications that explore the human biological mechanisms for links between early life factors (e.g. social/behavioral and physical) and childhood health data. Collaboration with a biostatistician is highly encouraged.

The UH3 phase should support:

• Prospective data and biospecimen collection of the cohort to test hypotheses of early life exposures on specific Focus Area child health outcomes
• Child development and health outcomes including patient/person reported outcomes for multi-cohort protocol
• DNA and/or other omic biospecimen collection and shipping to COREs, for multi-cohort protocol
• Exposure analyses through CHEAR or other comparable resources
• Risk modeling of multi-exposures to child health outcomes

Descriptions of Core Elements for Prospective Data Collection

All applicants should anticipate collecting Core elements in the prospective phase of ECHO funding support. Specific assays and measures will be delineated and standardized according to a multi-center protocol developed by the ECHO Steering Committee. This will be a collaborative effort between the PDs/PIs of the cohorts, the CC, DAC, COREs, and NIH Program Staff. If already present in cohorts upon inclusion into ECHO, the Core Elements will be harmonized across studies, as well.

Core Elements include:

• Demographics (e.g. race, ethnicity, gender, socioeconomic status, geographic location)
• Typical early development (e.g. growth, milestones, physical activity, sleep, and optional sub element-microbiome)
• Environmental exposures (e.g. physical, chemical, in-utero, microbial, psychosocial, natural and built environment)
• Genetics (genotyping to be provided by an ECHO Genetics Core and optional sub element-epigenetics)
• Patient/person (parent or surrogate) reported outcomes

To assist in the collection and analysis of these common data elements, the ECHO consortium will support centralized capabilities including a system for Patient/person Reported Outcomes, genotyping and analysis, and assessment of environmental factors in biospecimens. Collecting biospecimens suitable for studies of the microbiome and epigenetics also will be encouraged where appropriate.

Demographics

This FOA will support the collection of demographic information beyond basic information for parents and children (e.g. age, race/ethnicity, gender, socioeconomic status). Additional demographic information are encouraged, particularly those that are important to evaluate environmental exposures (e.g. geographic residential and/or daycare/school locations) and may be expanded for multi-cohort protocols once determined by the Steering Committee.

Typical Early Development

All children should be assessed on basic developmental, age-appropriate physical, cognitive, and social and emotional milestones, such as those recommended by the American Academy of Pediatrics. These assessments could be obtained through electronic health records (EHR), through observations that are included in the study, or via parent reports. An optional sub element is the microbiome.

Genetics

Genetics is a key component for fully understanding mechanisms underlying environmental exposures and the typical and atypical child development. Ideally, cohorts would already have biospecimens (e.g. buccal swabs, saliva, blood) from which DNA could be extracted and genotyped through participation in the ECHO consortium. If biospecimens are not available, appropriate consent for use, or existing biospecimens prove to be inadequate for genotyping, cohorts should anticipate collecting and genotyping such biospecimens as a part of the prospective ECHO data collection effort. At a minimum, ECHO plans to genotype the children in the cohort. If DNA samples are available through funded cohort studies, parent-child trios (or parents and children) may be genotyped. An optional sub-element is epigenetics.

Environmental Exposures

Environmental exposures can comprise a broad range of assessments, including those for chemical and non-chemical stressors. Applicants are strongly encouraged to include measures of both behavioral/social and physical environments. The goals of including multilevel environmental assessments include, but are not limited to:

• Hypothesis-driven targeted assessment of specific environmental factors and their links with childhood health outcomes.
• Agnostic evaluation of sets of environmental factors suspected of contributions without a specific hypothesis (such as the comparison of the relative impact of exposures to multiple classes of exposures such as metals, pesticides, and air pollution to neurodevelopmental endpoints)
• Hypothesis-free discovery of unknown or unanticipated contributions of environmental factors through the application of exposomics or other broad approach to discovery (untargeted metabolomics including exogenous and endogenous factors).

Examples of key behavioral/social environments include, but are not limited to:

Parents and/or children: smoking status, substance abuse, physical activity and diet, stress, depression, and other mental health conditions, education, overall Health Related Quality of Life, perceived family and peer support, parent-child relationships.

Examples of key chemical and non-chemical stressors include, but are not limited to:

Chemical stressors may be considered as single chemicals, or as mixtures and aggregates as may be found in consumer products used by children and environments frequented by children.

Non-chemical stressors include modifying factors such as diet and nutrition, physical activity including time spent in various microenvironments, psychosocial and socioeconomic factors, and the design of the built environment (e.g. settings: home, school, play areas) from birth through young adulthood.

The Children's Health Exposure Analysis Resource (CHEAR) http://www.niehs.nih.gov/research/supported/dert/programs/chear/ Core will provide laboratory and statistical analyses to add or expand the inclusion of environmental exposures in Pediatric Cohort research. The CHEAR Core (or similar resource) is strongly encouraged to provide

1) rigorous assessment of a range of environmental exposures, xenobiotics, physiological measurements, and other biological indicators of environmental exposure and response in biospecimens including typically collected biofluids (blood, serum, plasma, urine) as well as other biospecimens including hair, placenta, and deciduous teeth, and (2) statistical tools and data science approaches to manage and analyze all of these newly generated datasets in a cohesive and integrated manner. CHEAR and the ECHO CHEAR Core will enable the children's health research community, including ECHO investigators, to enhance and build on their existing studies by expanding the capability or capacity of measuring both chemical and non-chemical stressors that effect children's wellbeing and development. It is expected that by implementing standard measures and analyses across studies and encouraging collaborations and networking, the CHEAR Core will enable meta-analyses and integration of datasets of multiple cohorts and other study designs.

The output of these UG3/UH3 projects, to be facilitated by a CC (RFA-OD-16-006) and a DAC (RFA-OD-16-005), will be a collaborative group of extant pre- and peri- and post-natal cohorts that address the Core Elements, are prepared to address research questions related to the Focus Areas, but are also staged to work together to collect harmonized and standardized data focused on understanding pre-, peri- and post-natal environmental influences on child health and development.

Applicants should propose hypotheses on how early life environmental exposures affect child heath (including growth/development, clinical outcomes, and genetics) during the proposed prospective follow-up of the extant cohort.

Applicants should propose research relevant to one or more of the Focus Areas described above. Applicants should propose a single study design leveraging existing exposure data and /or biospecimens and additional prospective data collection of the cohort on focus area health outcome(s) and/or genetics to address a specific hypothesis of the role of environmental exposures on pediatric health outcomes. Patient reported outcomes are encouraged for key focus area applications. In addition, the Steering Committee will collaboratively identify PROs essential for collection across all cohorts. Applicants are encouraged to utilize PROMIS measures [see NIH-funded Patient-Reported Outcomes measures and functional assessments ("NIH Toolbox") at www.healthmeasures.net and NIH PhenX Toolkit: https://www.phenx.org/]

Assessment of environmental exposures is required, either via internal assessments (e.g. biological assays that quantify exposure levels in the body) or via external assessments (e.g. assays that quantify environmental exposure levels through mobile devices, geocoding, questionnaires). Environmental exposures include, but are not limited to, chemical exposures, biological (e.g. microbial/antigenic), social, behavioral, climate, built and physical environment. Applicants are strongly encouraged to leverage FY2015 resources CHEAR and PRISMs (

http://www.niehs.nih.gov/research/supported/dert/programs/chear/

http://www.nibib.nih.gov/funding/funding-opportunities/prisms ).The applicant should describe in the research plan when and what clinical data, biospecimens, and resources will be collected and analyzed during the longitudinal follow-up of the cohort.

All cohorts funded as part of ECHO must agree to participate in prospective data collection efforts and are expected to reserve a portion of their budget for these efforts. These prospective data collection efforts will be related to the Core Elements and Focus Areas, and will be developed and agreed upon by a Steering Committee comprising PDs/PIs of the CC, DAC, PRO Core, CHEAR Core, the Genetics Core, the IDeA States Pediatric Clinical Trials Network DCOC, and each of the Cohort sites, as well as the NIH ECHO Program Director and NIH Project Team during the first year of the awards. The DAC, along with assistance from the CC, will be charged with coordinating and implementing the data collection process (including informed consents, protocols, case report forms, MOPs after funding). All cohorts will be expected to participate in an initial startup meeting and other meetings among all cohorts, including Focus Area and Project Coordinator subcommittees of the SC. These meetings will focus on tasks related to harmonizing the cohorts and selection of prospective measurement.

Criteria for Transition

Performance metrics will be evaluated before the UG3 award is transitioned to the UH3 phase after the second year of funding. Final milestones will be designed during the first year of the UG3 planning phase. The application should specify the milestones for transition, which will be evaluated during peer review and used as the basis of programmatic review at the transition time.

It is suggested that applicants consider the demonstration of the following when developing milestones for the application:

• access to the data and biospecimens proposed in their application in the timeframe proposed;
• feasibility of data collection related to their study's proposed research question(s);
• relevant and good quality environmental exposure;
• involvement in designing and contributing to the prospective multi-cohort protocol; and
• appropriate participant consent for recontact and follow-up.

Other programmatic criteria that would affect the transition from the UG3 phase to UH3 phase include contributions to the larger goals of ECHO, the availability of NIH funds, NIH program priorities, and NIH leadership approval.

Selected Research Examples:

Research examples include, but are not limited to:

• What are the specific relative contributions of epigenetic, genetic, and environmental influences on child health?
• What is the measureable normal human variation (of key outcome variables) within the population and across the lifespan?
• What factors render individuals or populations subjected to the same exposures as resilient or susceptible to disease? Do these differ over time and by sex?
• What are the unknown elements of the human virome and how do interactions of the virome with the host and the rest of the microbiome affect child health and disease?
• What are the inflection points at which the body's normal physiologic equilibrium (homeostasis) becomes dysregulated, leading to the development of chronic diseases?
• What are the molecular and cellular physiologic characteristics of the innate and adaptive immune systems that promote health and prevent phenotypic expression of disease?
• What are the molecular and behavioral mechanisms involved in maintaining a healthy weight across the lifespan?
• What are the genetic, biomarker, and environmental predictors of risk for key focus areas of childhood outcome?

This FOA is intended to support only human studies. Applications that include animal studies will not be considered responsive. Patient registries alone, without a hypothesis to be tested, will not be responsive. Conduct of a new clinical trial is not the intent of this FOA, but an existing clinical trial cohort may be used if appropriate.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

PD(s)/PI(s) should possess a doctoral degree in a relevant field such as maternal and fetal medicine, neonatology, pediatrics, key focus area expertise, and is/are required to commit no less than 2.4 person-months (20 percent) combined effort to the ECHO Extant Cohort program. PDs/PIs must have clinical research and/or epidemiology expertise. Active participation of the PDs/PIs is expected during all phases of the ECHO clinical research study.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the "Apply for Grant Electronically" button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Erica L. Spotts, Ph.D.
Telephone: 301-402-1146
Fax: 301-402-1150
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exception: For this specific FOA, the Research Strategy section is limited to 30 pages.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Facilities & Other Resources: Describe the infrastructure available from the parent study.

All instructions in the SF424 (R&R) Application Guide must be followed.

One individual must be designated as an alternate PD/PI who is able to serve in the absence of the PD/PI. Multi-disciplinary teams are strongly encouraged with clinical research expertise in child development and/or health outcomes, epidemiology, exposure assessments. Personnel with expertise in data management of the extant cohort should be included if available. Key personnel should include Biostatistics expertise. Collaboration with a biostatistician is highly encouraged.

All instructions in the SF424 (R&R) Application Guide must be followed.

Applications should budget for the following:

• PD(s)/PI(s) will be required to declare a minimum effort of 2.4 person-months (20 percent) effort per year. Applications proposing Multiple PD(s)/PIs(s) must have a minimum combined PD/PI effort of 2.4 person months.
• Research coordinator(s) for IRB submission of protocol/consent forms, CRF development, Manual of Procedures development of single and multi-center protocols, training, and implementation of the protocol for longitudinal follow up of the cohort participants.
• Arrangement of logistical services for protocol-specific costs, including subcontracts and supplies.
• Support for the activities as member(s) of the Steering Committee, including in-person travel to Bethesda, MD at least four times a year throughout the project period, including the launch meeting anticipated in October 2016, in order to develop the multi-cohort protocol.

Multicenter Data Collection

Budgets must include no more than $1,200 total costs/subject/year for Key Focus Area specific clinical data and exposure assessments (non-overlapping with existing funding).

Budgets must include no more than $1,000 total costs/subject/year for ECHO-Core elements data and sample collection and transfer to the CC and Cores. Data collection and transfer to the CC for the multicenter protocol requirements (if awarded in future years) will be restricted and may be renegotiated based on performance, and will not be re-budgeted without NIH prior approval.

The budget for the first year, which includes a 9-month planning phase, should include a minimum of 2.4 calendar months effort for the applicant PD/PI or a minimum of 2.4 calendar months combined effort for all PD(s)PI(s) if the multiple PD/PI strategy is used, clinical study coordinator, extant cohort Coordinating Center Data Management PI and/or Project Manager, travel funds for four 2-day Steering Committee meetings in Bethesda, MD, for the PD/PI and coordinator, travel funds for 2-3 days of coordinator training, and additional items as needed.

There will be two types of costs that applicants need to consider: 1) resources provided for the existing cohort's own research, and 2) costs related to the Common Elements that will be collected for all participants in the consortium. The per enrolled/active participant, per year allowable cost for costs related to the Common Element data collection is up to $1000 in total costs.

For FY17-22 all costs required for the proposed research must be included in the application and be fully justified. The budget must include support for clinical study coordinators at sites where prospective follow up will be conducted; a minimum of 2.4 calendar months effort for the applicant PI or a minimum of 2.4 calendar months combined effort for all PDs/PIs if the multiple PD/PI strategy is used. The budget should include the costs associated with identification, screening, and recruitment of subjects and, if indicated, new subjects; the costs of obtaining, processing, and storage of biological specimens; and the costs associated with the analyses required for the physiologic and/or molecular/biologic aims of the research. Travel costs for four Steering Committee meetings per year in Bethesda should be included for several members of the Research Center. If CTSA resources are to be used, and a fee is charged, please note this in the budget.

The elements of patient-related research costs should be clearly identified, and included both as a per-subject amount, and a total amount. Subject-related funds can be moved by NIH after award from one site to another to adjust for variability in recruitment or other needs that might arise. Indirect costs (facilities and administration) are not permitted to be included in patient-related research costs. In addition, IRB fees are not permitted to be paid from direct costs in NIH grants. They are considered to be indirect costs.

For multicenter concept applications, the budget must include the costs associated with coordination of biospecimen collection from all patients to be recruited, not just the number of patients that are expected from the applicant site. Costs may include those associated with shipping specimens, images, or other material; staff time to develop operational and training manuals, analyze data, specimens, or images and report the results; any storage capability required at the sites; travel for four Steering Committee meeting per year in Bethesda, MD; and other components as required.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy

Applicants should propose and test new hypotheses (not already funded in the extant cohort) that explore child development and/or health response in one or more Focus Areas to various exposures by leveraging existing cohort data and biospecimens that can be completed in the UG3 phase (the secondary analyses) as well as the UH3 phase (the prospective data analyses). Applications proposing basic mechanistic studies should describe the utilization of samples from the human cohort(s). In addition to the standard background, significance, innovation, and approach that must be discussed in the Research Strategy, applicants should describe the population characteristics, data, and biospecimens available from the parent study and propose how any additional normal or at-risk participants, new data, and biospecimens to be collected will add to the ability to examine trajectories of health, risk, resilience, and disease. Applicants should propose how increasing sample size(s) through pooling data via the ECHO consortium could be leveraged to answer collaborative research questions on the impact of the environment on child health in the focus area of expertise.

The description of the planning period should include activities required to ensure that recruitment can begin by the end of FY16, such as finalizing protocols, obtaining pilot data if needed, obtaining IRB approval, establishing research collaborations with other sites, completing coordinator training, testing the feasibility/usability of existing biospecimens, assessing feasibility of recontact and/or reconsent, and ordering necessary supplies.

Applicants should detail what data and biospecimens they have available, over what period of time, for what ages, etc. Data relevant to the proposed research should be included in the body of the application. To be included are estimates of the number of participants for prospective follow-up, based on existing retention and potential attrition rates, and a timeline for enrollment and planned cohort-specific data collection.

All applications should provide a strategy to contact/recontact participants for enrollment in the longitudinal follow-up (including appropriate consent). This is particularly important in cases where the investigators are proposing to restart a closed study. In such instances, investigators are required to provide pilot data on the ability to recontact and enroll a sufficient portion of the participants, demonstrate that they could collect basic milestone data (e.g. height, weight, basic medical information) in the first funded year of the study, and provide a compelling argument for why restarting this study is critical for the overall data consortium effort. Applicants should provide a plan for expected data collection beginning in the first year of the funded study and minimum targets (milestones) to be achieved to qualify for second phase funding.

The research strategy for FY17-22 (the prospective phase of longitudinal data collection) should include a description of the clinical study design, including hypotheses, study objectives, target population, total number of subjects required at the site (for the research project) and across the ECHO Program (for the multicenter concept), anticipated duration of recruitment and data analysis, and a description of the statistical analysis plan. The Research Strategy should describe the patient population and recruitment resources including experience with recruitment and retention of children available at the Research Center site that would benefit the Program (e.g. CTSA, Maternal Fetal Medicine Unit, and/or Neonatal/Pediatric resources). The Research Strategy should propose specific milestones that will be used to evaluate success of the project throughout the duration of funding and particularly for evaluating the transition from UG3 to UH3 funding.

The research strategy should also detail how the specific cohort is important for the entire synthetic cohort effort and should include a proposal for simple validated data collection of incident disease outcome in one focus area that can be implemented across all cohorts (e.g. validated survey instrument for detection of incident asthma).

Applicants should propose how increasing sample size(s) through pooling clinical and environmental exposure data via the ECHO consortium could be leveraged to answer multi-cohort collaborative research questions on the impact of the environment on child health in the focus area of expertise and could easily be applied across all ECHO cohorts with anticipated subject population of ~50,000 children of various ages. This should include a strategy for prospective collection of environmental exposure measures relevant for ECHO multi-cohort protocol and health outcome measures.

The applicant institution and PD(s)/PI(s) should document clinical and research collaborative experience of the group as a whole in recruitment, and retention (at least 80%) of maternal/fetal, infant, and/or pediatric study participants in the extant cohort. Detailed data on the population available for each proposed study (retrospective and prospective single and multicenter) should be included. Clearly describe the formal organizational structure of the Research Group, including lines of authority and responsibility, with particular attention to the relationship of the organizational structure to ECHO's major objectives.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Resources generated by the ECHO Program are also expected to be widely shared with the Consortium and the broader scientific community for research. The Steering Committee will develop and implement Consortium-wide approaches for resource deposition and use, including submission to national repositories as appropriate. Resources include human biospecimens, instrumentation and assays, special standards, protocols, and bioinformatics tools.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is there a unique contribution of the existing cohort to the anticipated multi-cohort protocol of ~50,000 pediatric subjects? If not unique, what is the value of the cohort to the goals of ECHO (i.e. to leverage and build upon existing cohort infrastructure to investigate the role of early life exposures and underlying biological mechanisms in childhood health and disease; to identify critical periods of development that are impacted by multi-level exposures, and identify opportunities to mitigate risk of disease and maximize health)? If new data/specimen collection is proposed, is the value for examining trajectories of risk, resilience, and disease advanced? What is the likelihood that that concept could (or would) be applied across ECHO cohorts?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the PD/PI(s) have adequate expertise in and a documented history of contributions to the field of environmental exposures and child health outcomes? Does the PD/PI have prior experience with collaborative research? Does the PD/PI have prior experience with successful timely recruitment and retention of pediatric subjects? Will the investigators bring valuable areas of expertise to the ECHO program that will maximize flexibility for the program?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed? Are the UG3 milestones reasonable and appropriate? Does the research plan detail how the specific cohort would be important for the entire synthetic ECHO cohort effort and include a proposal for simple validated data collection of incident disease outcome in one focus area that could be implemented across all cohorts? Is there evidence of sufficient clinical data and biospecimen management, completeness, and quality to suggest significant contributions to the ECHO multi-cohort goals? Are the environmental exposures for targeted and untargeted analyses appropriate? Does the application specify milestones that adequately assess progress during the UG3 stage that would permit transition to the UH3 phase? If met, do these milestones provide adequate information to program staff to decide on funding the UH3 phase?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Is there evidence that the institution has a track record in supporting collaborative clinical investigations? Are there institutional resources that will be leveraged (CTSAs, networks, Cores)?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by CSR, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee's business official.

Awardees must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other DHHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Directing the activities of the ECHO Coordinating Center, including: (i) establishing and implementing processes for decision-making, communication and collaboration; (ii) establishing and implementing processes and systems for tracking the implementation of Center support functions, identifying problems/deficiencies, and determining the need for and implementing corrective actions; (iii) assessing and allocating resources, reviewing their adequacy, and determining needed adjustments; (iv) establishing and implementing financial management capacity and systems to track and project Center resources and expenditures; (v) implementing and managing an information system to support day-to-day Center activities; (vi) establishing and managing portals for study-specific documents/materials; (vii) reporting to and obtaining input from the ECHO Steering Committee (including the Executive Committee), the External Scientific Board, the ECHO Data Analysis Center PD/PI, the ECHO Genetics Core PD/PI, the ECHO PRO Core PD/PI, the ECHO CHEAR Core PD/PI, the ECHO Pediatric Cohort site PDs/PIs, and the IDeA States Pediatric Clinical Trials Network DCOC PD/PI; and (viii) establishing procedures and metrics for assessing Center progress and productivity
• Providing the full scope of ECHO coordination support including standardization, quality assurance and quality control for the collection of core outcomes by all ECHO Pediatric Cohort sites; ensuring appropriate handling and tabulation for biospecimens to be transferred to central ECHO laboratories and for biospecimens to be stored in biorepositories; ensuring appropriate and effective coordination and collaboration with the NIH ECHO Program Director and the NIH ECHO Team, the ECHO Steering Committee, the ECHO Data Analysis Center PD/PI, the ECHO Genetics Core PD/PI, the ECHO PRO Core PD/PI, the ECHO CHEAR Core PD/PI, and the ECHO Pediatric Cohorts PDs/PIs (across all ECHO cohorts and within ECHO scientific focus areas); and ensuring that the performance of support functions complies with all Federal and, where appropriate, country-specific regulatory requirements and guidelines for the conduct of human subjects research, as well as NIH policies and procedures.
• Providing reports to the NIH ECHO Program Director and the NIH ECHO Team regarding Coordinating Center and overall ECHO activities (e.g. tabular summaries of study progress, protocol deviation and site monitoring reports), as well as budgetary summaries as requested.
• Ensuring the appropriate training/certification of Pediatric Cohort staff designated to provide support, and including a list of all training programs and written assessments in the Annual Progress Report.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

NIH assistance to the ECHO operations will be provided by the ECHO Program Director and the NIH ECHO Team, as well as by NIH Project Scientists or other NIH staff that may be assigned to across-ECHO studies or studies within one of the four ECHO scientific focus areas. NIH staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond the normal program stewardship role for grants. It is anticipated that decisions regarding the Pediatric Cohort activities will be reached by consensus and that the NIH staff members will participate in this process. In various matters related to study approval and oversight, the NIH staff will have final decision authority, as described below.

• Concept Proposals and Study Protocols: NIH Project Scientists will: (i) participate in the development, review and approval of the concept proposals and research protocols of all across-ECHO studies and of ECHO-supported studies that will entail a particular ECHO scientific focus area; (ii) provide final approval prior to initiation for across-ECHO studies as well as for ECHO-supported studies within each ECHO scientific focus area; (iii) approve timelines for protocol development, implementation and completion; (iv) participate in the data analysis process and the development of manuscripts resulting from ECHO-supported studies.
• Study Monitoring and Management: (i) The NIH ECHO Team and NIH Project Scientists, through the ECHO Coordinating Center, will monitor compliance with OHRP and NIH requirements for human subject research, accurate protocol implementation and internal quality assurance across all ECHO-supported studies. This includes: participating in the development of and approving Data and Safety Monitoring Plans prior to study initiation; determining the need to conduct for-cause clinical site visits, participating in such visits, and approving recommendations for remedial actions. (ii) NIH staff will participate in ECHO Study Management Teams to manage the day-to-day implementation of ECHO-supported studies that will be conducted across all ECHO Pediatric Cohorts or across-Cohort studies that address an ECHO scientific focus area.
• IND/IDE Sponsorship: Aside from the IDeA States Pediatric Clinical Trials Network, the ECHO Pediatric Cohort sites are not likely to conduct clinical trials requiring IND/IDE sponsorship. However, in the rare event that this becomes a necessity, the ECHO NIH Program Director will determine on a case by case basis whether the regulatory sponsor for a clinical trial conducted under IND/IDE will be an NIH IC or an ECHO Pediatric Cohort Investigator. If the regulatory sponsorship responsibility is assigned to a NIH IC, NIH Project Scientists/Medical Monitors will obtain, through the ECHO Coordinating Center and the ECHO Data Analysis Center, regular reports on serious adverse events and protocol deviations, and will decide on the final disposition of SAE Reports for all IND/IDE studies.
• Study Termination: NIH reserves the right to terminate, curtail or suspend an ECHO-supported study for any reason, including but not limited to risks to subject safety, occurrence of unforeseen safety or ethical issues, scientific question is no longer relevant or the objectives will not be met, failure to comply with Federal regulations or Terms and Conditions of Award, and reaching a major study endpoint before schedule with persuasive statistical significance.
• Access to Data: The NIH ECHO Team and NIH Project Scientists will have the right of access to all data (raw and analyzed) generated under this cooperative agreement and may periodically review these data.
• Grant Stewardship: Additionally, a NIH program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• The ECHO NIH Program Director will establish an ECHO External Scientific Board. The External Scientific Board will submit its recommendations to the ECHO NIH Program Director, who will then inform the members of the ECHO Steering Committee. Recommendations by the External Scientific Board are advisory.

Areas of Joint Responsibility include:

• The NIH ECHO Program Director and the NIH ECHO Team, in collaboration with the PDs/PIs of all ECHO awards, will participate in deliberations and decision-making regarding the multiple substantive, operational, financial and administrative responsibilities of this NIH initiative.
• NIH Project Scientists and/or their designees will collaborate with ECHO Coordinating Center staff to ensure the provision of appropriate information, materials and training regarding NIH policies and procedures for the conduct of human subject research.
• Close interactions amongst the awardee, awardees from the companion FOAs, and NIH will be required. Shortly after the award, the PDs/PIs and NIH program staff will form the ECHO Steering Committee, which ultimately will report to the NIH Director

ECHO Steering Committee

• The ECHO Steering Committee will be co-chaired by the NIH ECHO Program Director, the PI/PD of the Coordinating Center, and the PI/PD of the Data Analysis Center. It also will be composed of the PIs/PDs of the PRO Core, CHEAR Core, the Genetics Core, the IDeA States Pediatric Clinical Trials Network DCOC, and each of the cohort sites, who all will have 1 vote. The NIH ECHO Program Director and the NIH ECHO Team will serve as non-voting members of the ECHO Steering Committee.
• An Executive Committee of the Steering Committee also will be established, and will be composed of the three co-chairs and a representative from each of the funded elements one each from the PRO Core, the Genetics Core, CHEAR Core, and the IDeA States Pediatric Clinical Trials Network DCOC, as well as one PI/PD collectively representing the cohort sites.
• The Executive Committee will invite expert consultants as needed, coordinate with the External Scientific Board, assist as necessary with annual progress reports, and appoint and charge members of subcommittees
• These subcommittees will facilitate development, implementation, and monitoring of specific ECHO functions as needed. Suggested subcommittees include:
  • Data Measurement and Sharing: members from each cohort site, the CC, the DAC, and the PRO Core; responsible for selecting core measures and establishing protocols for data collection, quality control (QC), and sharing; CC and DAC would implement the protocols, conduct training and QC, etc.
  • Biostatistics and Design: members from each cohort site, the CC, the DAC, and the PRO Core; responsible for (1) developing analysis plans for each of the core measures, including biospecimens and environmental samples, (2) reviewing and providing advice on the analysis plans for each of the participating cohorts, (3) conducting methods research based on issues that arise during the course of the project, (4) serve as a consulting body for any of the PDs/PIs seeking input on analysis issues
  • Publications: members from each cohort site, CC, DAC, and the PRO Core; responsible for developing publication policies and procedures, review of abstract and manuscript proposals for cross-project papers and presentations, review of proposed ancillary studies, and review of proposed pilot studies
  • Focus Areas: members from the cohorts in each Focus Area and the CC; separate subcommittees for each of the 4 Focus Areas to support regular interactions among investigators interested in the same Focus Areas
  • Project Coordinators: members would include the coordinators from the cohort sites and a CC representative; meet regularly for exchange of information about their studies, and help each other identify best practices for a variety of logistical issues including retention, training, data collection, etc.
  • IDeA States Network: members from the participating IDeA states sites, IDeA states DCOC, and the CC; meeting regularly for exchange of information about their projects, best practices, etc.
• Key personnel will be expected to serve on subcommittees, as appropriate, according to their expertise.
• The Steering Committee will meet in person quarterly during the first year and at least annually thereafter. Monthly teleconferences will be held for the Steering Committee and its subcommittees, and these may be more frequent at times to facilitate planning, etc. The Coordinating Center (CC) will be responsible for arranging and facilitating the meeting and teleconferences. Applicants should plan to attend an initial planning meeting of the Steering Committee in Bethesda, Maryland in fall 2016.
• The Steering Committee will have responsibility for developing the overall scientific direction of the program; assuring compliance with program policies and procedures; designing study protocols; implementing studies; ensuring data quality and completeness; planning for analysis and interpretation of data; and reporting results in presentations and publications.
• The Steering Committee must work cooperatively and interactively during the first year to develop the final protocols and all of the materials necessary to begin the prospective human studies within 12-18 months after award. The final plan, with a study timeline and milestones, will be submitted and must be approved by the NIH ECHO Program Director and the NIH Director, with involvement of the NIH ECHO Team and relevant IC program staff, before the second year of funds will be awarded.
• First year planning activities include, but are not limited to:
• Developing clinical and laboratory protocols and plans for data collection and management
• Standardizing collection of core data elements
• Overseeing plans to address the various bio-ethical issues and concerns (e.g., handling of sensitive data, participatory risk, involvement of vulnerable populations, incidental findings) that are likely to arise during the conduct of the research
• Obtaining approvals as needed at the ECHO Pediatric Cohort site institutions, such as IRB approvals
• Preparing a Manual of Operations with primary responsibility residing with the CC
• Developing a detailed plan for storage and shipping of all biospecimens
• Developing detailed plans for the thorough analysis of data
• Agreeing to abide by a common data sharing plan
• Developing a detailed timeline with concrete milestones for the entire study

External Scientific Board

• Five to seven external experts will serve as the External Scientific Board (ESB), and will be selected and appointed by the NIH ECHO Program Director and NIH Director.
• The ESB will review and offer input on ECHO structure, function, and studies, both during protocol development and during the analysis of results. Members of the Board will provide input based on their individual areas of expertise, as needed over the course of the program. They will assist the NIH regarding processes and substantive issues that arise during the project and will help ensure that the resources to be delivered by the program are as useful as possible for the end users.
• External Scientific Board members may be invited to attend some ECHO Steering Committee meetings.

Data and Safety Monitoring Board

• In the event the ECHO activities include clinical trials, an independent Data and Safety Monitoring Board (DSMB) will be established to monitor and provide recommendations to the NIH regarding participant recruitment/enrollment, safety, data quality, and other issues, as appropriate. The DSMB will also review the Steering Committee-approved common protocol, informed consent templates, milestones, and monitoring plans prior to the start of recruitment. It is recommended that, if possible, a single central Institutional Review Board (IRB) is used to streamline the protocol approval process and to standardize the monitoring of human subjects' protection in the ECHO program.

Development of Milestones

• Because this Consortium will require specific achievable goals (e.g., timely recruitment of participants, expected annual throughput), milestones should be proposed by the applicant. Milestones are goals that are quantifiable for measuring success, and include associated annual or semi-annual quantitative criteria.
• Final milestones will be designed during the first year in the planning phase. After review and approval by the NIH, the final set of approved milestones will be specified in the Notice of Award.
• Progress towards achieving the final set of milestones will be evaluated by NIH program staff on an annual basis. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, the project does not meet the milestones, funding for the project may be either restricted or discontinued.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the ECHO awards) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The panel members will be a designee of the ECHO Steering Committee, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)

Telephone: 301-710-0267

Erica L. Spotts, Ph.D.
Office of Behavioral and Social Sciences Research (OBSSR)
Telephone: 301-402-1146
Email: [email protected]

Carol J. Blaisdell, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: [email protected]

Tara A. Schwetz, PhD
Office of the Director (OD)
Telephone: 301-451-5064
Email: [email protected]

Valerie Durrant, Ph.D.
Center for Scientific Research
Telephone: 301-827-6390
Email: [email protected]

Donna R. Sullivan
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2979
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.